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| MODERN RESEARCH ON CHINESE MATERIA MEDICA |
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| Year : 2016 | Volume
: 2
| Issue : 4 | Page : 29-37 |
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Metabolites identification of curcumin, demethoxycurcumin and bisdemethoxycurcumin in rats after oral administration of nanoparticle formulations by liquid chromatography coupled with mass spectrometry
Rui Li1, Qi Wang2, Jing-Ran Fan3, Jun-Bin He2, Xue Qiao2, Cheng Xiang2, De-An Guo2, Min Yea2
1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China; Key Laboratory of Food Biotechnology of Sichuan Province, School of Bioengineering, Xihua University, Chengdu 610039, China
2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| Date of Submission | 16-Aug-2016 |
| Date of Acceptance | 28-Sep-2016 |
| Date of Web Publication | 10-Sep-2020 |
Correspondence Address:
Min Yea
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
38 Xueyuan Road, Beijing 100191
China
 Source of Support: None, Conflict of Interest: None  | 4 |
DOI: 10.15806/j.issn.2311-8571.2016.0035
Background: Curcuminoids are promising cancer chemopreventive agents. Curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the major bioactive curcuminoids in turmeric. However, comprehensive metabolic studies of these three curcuminoids are still limited.
Objective: To identify the metabolites of curcumin, DMC and BDMC in rats after oral administration of solid lipid nanoparticles (SLNs).
Methods: Male Sprague-Dawley rats (250 ± 20 g, body weight) were randomly divided into 4 groups (n=3), and were orally administered with curcumin-SLN, DMC-SLN, BDMC-SLN, or blank-SLN, respectively. Plasma samples (500 μL) via the angular vein were collected at 1, 2 and 4 h post dosing, and the urine and feces samples were collected at 0-12 h and 12-24 h post-intake. An HPLC-DAD-ESI-MSn method was developed to identify the metabolites. The structures of phase II metabolites were further confirmed by enzyme hydrolysis.
Results: A total of 34 metabolites were identified in rats plasma, urine, and feces. Most of them were phase II metabolites, including glucuronide conjugates and sulfate conjugates. Among them, the glucuronide conjugates were the major metabolites in rats plasma. In the meanwhile, the three parent curcuminoids were detected in high amounts in the urine and feces samples.
Conclusion: The possible metabolic pathways of curcuminoids in rats were proposed.
Abbreviations: DMC: Demethoxycurcumin; BDMC: Bisdemethoxycurcumin; SLNs: Solid lipid nanoparticles; HPLC-DAD-ESI-MSn: High- performance liquid chromatography coupled with diode array detection and electrospray ionization tandem mass spectrometry
Keywords: Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin, Solid lipid nanoparticles, Metabolic pathway
How to cite this article:
Li R, Wang Q, Fan JR, He JB, Qiao X, Xiang C, Guo DA, Yea M. Metabolites identification of curcumin, demethoxycurcumin and bisdemethoxycurcumin in rats after oral administration of nanoparticle formulations by liquid chromatography coupled with mass spectrometry. World J Tradit Chin Med 2016;2:29-37 |
How to cite this URL:
Li R, Wang Q, Fan JR, He JB, Qiao X, Xiang C, Guo DA, Yea M. Metabolites identification of curcumin, demethoxycurcumin and bisdemethoxycurcumin in rats after oral administration of nanoparticle formulations by liquid chromatography coupled with mass spectrometry. World J Tradit Chin Med [serial online] 2016 [cited 2023 Dec 1];2:29-37. Available from: https://www.wjtcm.net/text.asp?2016/2/4/29/294715 |
| Introduction | |  |
Curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the major bioactive compounds of turmeric, which is derived from the rhizomes of Curcuma longa. For a long time, turmeric has been extensively used as a coloring and flavoring agent in different countries. In recent years, these curcuminoids have been considered as novel natural agents for the treatment and prevention of cancer. They possess a variety of significant biological activities, including antioxidant[1],[2], anti-diabetes[3], antimicrobial, anti-Alzheimer’s disease[4],[5], anti-inflammatory, and anti-tumorigenesis activities[6],[7].
A number of studies have tried to reveal the in vivo metabolism of curcuminoids[8],[9],[10]. Detection of the parent compounds and their metabolites has been challenging due to poor bioavailability. Nanoparticle formulations have been reported to enhance water solubility and bioavailability of curcumin[11],[12],[13]. Recently, our group studied the pharmacoki- netics of curcuminoids in mice tumor after oral administration of solid lipid nanoparticles (SLNs)[14]. The curcuminoids could be detected in tumor tissues at relatively high concentrations (Cmax between 24-285 ng/mL). However, the metabolism of curcuminoids after oral administration of SLNs has not been comprehensively studied.
Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 81222054 and 81302742), State Administration of Traditional Chinese Medicine (No. 201307002), and the Key Research Project of Department of Education of Sichuan (11ZA005).
In this work, we identified the metabolites of curcumin, DMC, and BDMC in rats plasma, urine and feces samples after oral administration of their SLNs by a sensitive high- performance liquid chromatography coupled with diode array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI-MSn) method. The metabolic pathways of curcuminoids were also proposed.
| Methods | | |
1. Chemicals and reagents
Pure curcuminoids including curcumin, DMC and BDMC were isolated from the rhizomes of Curcuma longa by the authors[6]. The preparation and characterization of three curcuminoids loaded SLNs (curcumin-SLNs, DMC-SLNs, BDMC-SLNs, and blank-SLNs) had been reported in our recent publication[14]. /β-Glucuronidase and sulfatase (Type HP-I from Helixa pomatia) was purchased from Sigma (St. Louis, MO). HPLC grade acetonitrile (J.T. Baker, Phillipsburg, NJ, USA) was used for LC/MS analysis. Deionized water was purified by Milli-Q system (Millipore, Bedford, MA, U.S.A.). The chemical reagents for extration were of analytical-reagent grade and were purchased from Beijing Chemical Corporation (Beijing, China).
2. Animals and drug administration
Male Sprague-Dawley rats (250 ± 20 g, body weight) were obtained from the Laboratory Animal Center of Peking University Health Science Center, China. The rats were housed in an animal room in controlled condition of (22~24 °C) with food and deionized water. To collect the feces and urine samples, animals were held in a stainless steel metabolism cage and fasted for 12 h before experiments, but were given access to deionized water. All animal treatments were strictly in accordance with the National Institutes of Health Guide to the Care and Use of Laboratory Animals. The experiments were carried out with approval of the Committee of Experiment Administration of Peking University Health Science Center. The rats were randomly divided into four groups (n=3), and were orally administered with curcumin-SLNs, DMC-SLNs, BDMC-SLNs, and blank-SLNs, respectively, at a dose of 100 mg/kg body weight (2.5 mL per rat).
3. Sample collection
Blood samples via the angular vein were collected into heparinized tubes at 1, 2 and 4 h post dosing and immediately centrifuged at 9000 rpm for 10 min to obtain the plasma. The urine and feces samples were collected at 0-12 h and 12-24 h after drug administration. All the samples were stored at -80 °C before treatment.
4. Sample preparation
The plasma samples (300 μL) were mixed with 1200 μL acetonitrile by vortexing for 5 min, and then centrifuged at 9000 rpm for 10 min. The supernatant was transferred to a clean test tube and dried under a gentle flow of nitrogen gas at 35 °C. The residue was reconstituted in 200 μL methanol. After filtering through a membrane (0.22-μm pore size), a 50-μL aliquot was injected for analysis.
The urine samples (2 ml) were mixed with ethyl acetate at the ratio of 1:4 (v/v) for three times. After vortexing for 5 min, the sample was centrifuged at 9000 rpm for 10 min, and the upper layer (ethyl acetate soluble fraction) was transferred to a clean test tube and dried under a gentle flow of nitrogen gas at 35 °C. The residue was reconstituted in 200 μL methanol. After filtering through a membrane (0.22-μm pore size), a 50-μL aliquot was injected for analysis.
The feces samples (2 g) were extracted with 20 ml of methanol in an ultrasonic bath for 60 min, and then centrifuged at 9000 rpm for 5 min. After filtering through a membrane (0.22-μm pore size), a 50-μL aliquot was injected for analysis.
5. Enzyme hydrolysis
An aliquot of the treated plasma or urine sample (50 μL) was dried under nitrogen gas and mixed with 200 μL β-glucuronidase solution (containing 14.5 U/μL, in sodium acetate buffer, pH 5.5). The mixture was incubated at 37 °C for 5 h, and then added with 800 μL methanol-acetonitrile (2:1), vortexed and centrifuged at 13,500 rpm for 10 min. The supernatant was dried under nitrogen gas stream and the residue was dissolved in 200 μL of methanol. After filtering through a membrane (0.22-μm pore size), a 50-μL aliquot was injected for analysis.
6. HPLC-DAD-ESI-MS” analysis
The analyses were performed using an Agilent Series 1100 HPLC instrument equipped with a diode-array detector (Agilent Technologies, Palo Alto, CA, USA). The samples were separated on a YMC Pack-ODS A C18 column (4.6 mm x 250 mm, 5 μm) protected with an Agilent Zorbax SB-C18 guard column (4.6 mm x 12.5 mm, 5 μm). The mobile phase consisted of acetonitrile (A) and 0.1% aqueous formic acid (B). The gradient elution program was as follows: 0 min, 5% A; 30 min, 45% A; 50 min, 95% A; 55 min, 95% A. The flow rate was 1 mL/min, and the column temperature was maintained at 30 °C.
A Finnigan LCQ Advantage ion trap mass spectrometer (Thermo Finnigan, San Jose, CA, USA) was connected to the Agilent 1100 HPLC system via an ESI source in a post- column splitting ratio of 3:1. Ultra-high purity helium (He) was used as the collision gas and high purity nitrogen (N2) as the nebulizing gas. For negative ESI analysis, the optimized parameters were as follows: sheath gas (N2), 50 arbitrary units; auxiliary gas (N2), 10 units; ion spray voltage, 4.0 kV; capillary temperature, 330 °C; capillary voltage, 35 V; tube lens offset voltage, -40 V; source-fragmentation voltage, 10 V; For full-scan MS analysis, the spectra were recorded in the range of m/z 120-1200. Data-dependent acquisition was used so that the two most abundant ions in each MS scan were selected in turn. The collision energy for CID was adjusted at 35% in analysis and the isolation width of precursor ions was 2.0 mass units.
| Results | | |
1. Identification of metabolites from curcumin
A total of five phase II metabolites were identified from rat plasma after oral administration of curcumin-SLNs, including M3 ([M-H]-m/z 631), M6 ([M-H]-m/z 629), M9 ([M-H]-m/z 627), M12 ([M-H]-m/z 623), and M15 ([M- H]-m/z 543) [Figure 1]. For the parent drug curcumin, its pseudomolecular ion m/z 367 ([M-H]-) yielded fragments at m/z 217 and m/z 173 (Table 1). The MS/MS spectra for M12 showed the [M-H-gluA]- ion at m/z 447 (gluA represents glucuronic acid residue, C6H8O6) and [M-H-SO3]- ion at m/z 543, and M15 showed the fragment ion [M-H-gluA]- at m/z 367. They were tentatively identified as curcumin-O- glucuronide-O-sulfate and curcumin-O-glucuronide, respectively. For M3, M6 and M9, the maximal UV absorbance was 278-280 nm, indicating they were hydrogenated metabolites. Upon collision-induced dissociation, M9 generated the fragment ions [M-H-gluA]- at m/z 451 and [M-H-SO3]- at m/z 547. The MS3 spectrum showed the aglycone ion at m/z 371 due to elimination of both glucuronide group and sulfate group, indicating the aglycone could be tetrahydrocurcumin. Thus, M9 was tentatively identified as tetrahydrocurcumin- O-glucuronide-O-sulfate. For M3, the characteristic neutral losses of gluA (176 Da) and SO3 (80 Da) were also observed, and the aglycone ion appeared at m/z 375. M3 was tentatively identified as octahydrocurcumin-O-glucuronide-O-sulfate. The MS/MS spectrum for M6 showed abundant [M-H- gluA]- ion at m/z 453 and [M-H-SO3]- ion at m/z 549. After being treated with β-glucuronidase, the peak for M6 disappeared. And the aglycone showed an [M-H]- ion at m/z 373, corresponding to hexahydrocurcumin. Thus, M6 was tentatively identified as hexahydrocurcumin-O-glucuronide- O-sulfate. | Figure 1: UV (425 nm) and TIC chromatograms of plasma and urine samples after oral administration of curcumin-SLNs, DMC-SLNs, BDMC-SLNs, and blank-SLNs. Peak numbers in the profiles were consistent with those shown in Table 1.
Click here to view |
In urine and feces samples, the parent compound curcumin (M34) was unambiguously identified according to the retention time and MS/MS spectra. The sulfated conjugates M20 ([M-H]-m/z 455), M24 ([M-H]-m/z 453) and M28 ([M-H]-m/z 447) were present in urine and/or feces samples. Their MS/MS spectra all showed an abundant [M-H-SO3]- fragment ion. M20, M28, and M24 were tentatively identified as octahydrocurcumin-O-sulfate, curcumin-O-sulfate, and hexahydrocurcumin-O-sulfate, respectively. M31 ([M-H]-m/z 369) was detected in both feces and urine samples, and was identified as the phase I metabolite dihydrocurcumin. The MS/MS fragment ions (m/z 219 and m/z 175) of M31 were consistent with previous reports[15],[16],[17].
2. Identification of metabolites from DMC
As shown in [Figure 1], five Phase II metabolites were detected in rats plasma after oral administration of DMC-SLNs, including M2 ([M-H]-m/z 601), M5 ([M-H]-m/z 599), M8 ([M-H]-m/z 597), M11 ([M-H]-m/z 593), and M14 ([M-H]-m/z 513). In the MS/MS spectra, DMC generated the typical fragment ions at m/z 337, 217, and 173. The characteristic neutral losses of gluA (176 Da) and SO3 (80 Da) were observed for M11, and the neutral loss of gluA was observed for M14. M11 and M14 were tentatively identified as demethoxycurcumin-O-glucuronide-O-sulfate and demethoxycurcumin-O-glucuronide, respectively. The characteristic neutral losses of gluA (176 Da) and SO3 (80 Da) were observed for M2, M5 and M8, due to cleavage of glucuronide group and sulfate group. Their aglycone ions appeared at m/z 345, 343, and 341, respectively, corresponding to octahydrodemethoxycurcumin, hexahydrodemethox- ycurcumin, and tetrahydrodemethoxycurcumin. The peaks for M2, M5 and M8 would disappear after the treatment of β-glucuronidase or sulfatase. Therefore, M2, M5 and M8 were tentatively identified as octahydrodemethoxycurcumin- O-glucuronide-O-sulfate, hexahydrodemethoxycurcumin-O- glucuronide-O-sulfate and tetrahydrodemethoxycurcumin- O-glucuronide-O-sulfate, respectively.
In the urine and feces samples, the parent compound DMC (M33) was identified by comparing the retention time and MS/MS spectra with an authentic standard. Upon collision-induced dissociation, the [M-H]- ion at m/z 339 for M30 produced fragment ions at m/z 219, 338, and 189. M30 was identified as dihydrodemethoxycurcumin. A total of eight phase II metabolites (M17, M18, M22, M23, M19, M30, M25 and M27) were detected from urine. M22 and M23 both showed a quasi-molecular ion of [M-H]- at m/z 423, and a product ion [M-H-SO3]- at m/z 343 [Figure 2]. Thus, M22 and M23 were tentatively identified as two isomers of hexahydrodemethoxycurcumin-O-sulfate. M22 showed MS/MS fragmentation transitions of m/z 423→259→179 and m/z 423→273→193. In contrast, M23 showed fragmentations of m/z 423→229→149 and m/z 423→ 243→163, indicating the sulfate group was located at the other side of the heptane chain. Moreover, the stronger signal of M23 indicated that it was more liable to form as a metabolite than M22, due to the steric hindrance of sulfate group and methoxy group. Simiarly, M17, M18 and M19 were identified as three isomers of octahydrodemethoxycur- cumin-O-sulfate. M25 showed the MS/MS fragmentation transitions of m/z 419→339→233→218 and m/z 339→189, whereas M27 showed fragmentations of m/z 417→337→ 217→173 and m/z 337→187→143. These fragments were identical with previous reports [10,18-19]. Thus, M25 and M27 were identified as dihydrodemethoxycurcumin-O-sulfate and demethoxycurcumin-O-sulfate, respectively. | Figure 2: Structural identification of the isomers M22 and M23. (A) HPLC/UV chromatogram of the rats urine sample (orally administered with DMCSLNs). (B) Extracted ion chromatograms (XIC) of M22 and M23. (C) (-) ESI-MSn spectra.
Click here to view |
3. Identification of metabolites from BDMC
A total of five phase II metabolites were detected in rats plasma after oral administration of BDMC-SLNs, including M1 ([M-H]-m/z 571), M4 ([M-H]-m/z 569), M7 ([M-H]-m/z 567), M10 ([M-H]-m/z 563), and M13 ([M-H]-m/z 483). M1, M4, M7 and M10 were characterized as conjugates with both glucuronic acid and sulfuric acid owing to the presence of characteristic neutral loss of gluA (176 Da) and SO3 (80 Da). M13 was a glucuronide conjugate due to the neutral loss of gluA (176 Da). In the MS/MS spectrum for M13, the [M-H-gluA]- ion at m/z 307 was observed, which could further fragment into m/z 187 and 143. It was tentatively identified as bisdemethoxycurcumin-O-glucuronide. Similarly, M10 was characterized as bisdemethoxycurcumin-O- glucuronide-O-sulfate. M1, M4 and M7 showed a product ion [M-H-gluA-SO3]- at m/z 315, m/z 313, and m/z 311, respectively. Their structures were tentatively identified as octahydrobisdemethoxycurcumin-O-glucuronide-O-sulfate, hexahydrobisdemethoxycurcumin-O-glucuronide-O-sulfate and tetrahydrobisdemethoxycurcumin-O-glucuronide- O- sulfate, respectively.
In the urine and feces samples, the parent compound BDMC (M32) was identified by comparing the retention time and MS/MS spectra with an authentic standard. Three phase II metabolites (M16, M21 and M26) were also detected from the urine sample. They showed [M-H-SO3]- ions at m/z 315, m/z 313, and m/z 307, respectively, suggesting their structures of octahydrobisdemethoxycurcumin-O-sulfate, hexahydrobisdemethoxycurcumin-O-sulfate, and bisde- methoxycurcumin-O-sulfate. M29 ([M-H]-m/z 309) was also detected in the urine sample, and was identified as the phase I metabolite dihydrobisdemethoxycurcumin.
| Discussion | | |
Curcuminoids, including curcumin, DMC and BDMC, are the major bioactive compounds of turmeric. In this work, we prepared SLNs of these pure compounds, and identified their metabolites in rats after oral administration by HPLC-DAD- ESI-MSn analysis.
Aside from the three parent curcuminoids, a total of 31 biotransformed metabolites were detected in the plasma, urine, and feces samples (Table 1). Among them, M1-M28 were phase II metabolites (glucuronide conjugates and sulfate conjugates). M29-M31 were dihydrogenated phase I metabolites. The metabolic reactions involved hydrogenation, glucuronidation, and sulfation. Based on the structures of the metabolties, metabolic pathways for the three curcumi- noids were proposed as shown in [Figure 3]. | Figure 3: Proposed metabolic pathways after oral administration of curcuminoids.
Click here to view |
The mono-glucuronide conjugates (M13, M14 and M15) were the major metabolites in plasma, indicating glucur- onidation was the major metabolic route for all the three curcuminoids. However, they were not detected in the urine or feces samples. On the other hand, the three parent compounds were not detected in the plasma samples, but were present in high abundances in the urine and feces samples. Our previous study had also indicated the parent compounds showed high concentrations in tumor tis- sues[14]. The relative abundances of curcuminoids and their metabolites in different tissues may be closely related with their pharmacological activities. Thus, mechanism for their in vivo biotransformation warrants more intensive studies in the future.
| Conclusion | | |
The metabolism of curcuminoids in rats was studied after oral administration of nanoparticle formulations. A total of 34 metabolites were tentatively identified by HPLC-DAD- ESI-MSn analysis and enzyme hydrolysis from the plasma, urine and feces samples. The major metabolic reactions involved glucuronidation, sulfation, and hydrogenation. The curcuminoids occured mainly as glucuronide conjugates in rat plasma, and the parent compounds were present in high abundances in the urine and feces. Based on these results, the metabolic pathways for curcuminoids in rats were proposed.
Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 81222054 and 81302742), State Administration of Traditional Chinese Medicine (No. 201307002), and the Key Research Project of Department of Education of Sichuan (11ZA005).
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[Figure 1], [Figure 2], [Figure 3]
[Table 1]
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